The objectives of this research are to provide physiological and pharmacological analyses of the synaptic organization of pathways from the rat basal forebrain to the limbic system and thalamus, and reciprocal projections from the limbic system to the basal forebrain. First, physiological studies of efferent projections from the rat basal forebrain will be continued. Work will concentrate on projections from the nucleus of the diagonal band of Broca, substantia innominata, and adjacent basal forebrain to the thalamic mediodorsal and reticular nuclei. In order to achieve this objective, the basal forebrain will be stimulated electrically, and synaptic potentials in response to this stimulation will be recorded intracellularly in the thalamus. Target cells will be identified by intracellular HRP injection. Second, a pharmacological analysis will be performed, studying putative cholinergic projections from the basal forebrain to limbic cortex (specifically entorhinal cortex, subicular complex, and cingulate cortex); and thalamus (specifically entorhinal cortex, subicular complex, and cingulate cortex); and thalamus (specifically the mediodorsal and reticular nuclei). It is hypothesized that target principal cells are excited via slow- acting M1 muscarinic receptors. Cholinergic agonists and antagonists will be iontophoretically applied during electrical stimulation of the basal forebrain. The effect of stimulation will be compared to the action of the cholinergic agonists, and the efficacy of the cholinergic antagonists in blocking the evoked synaptic will be determined. Third, the physiological action of projections to the nucleus of the diagonal band from the subicular complex will be determined. Since the physiological action of this projection is unknown, in vivo intracellular recording experiments will be valuable in establishing the synaptic action of the limbic cortex on diagonal band neurons. These intracellular and pharmacological studies attack problems that can best be studied at the systems level in the intact, in vivo preparation. The cholinergic cell of the basal forebrain, and their limbic targets appear to undergo degeneration in Alzheimer's disease. An understanding of this neuronal system can therefore provide insight into the psychopathology associated with this disease.
